Although it is known that thyroid disease and cardiovascular health are closely linked, the cardiovascular consequences of thyroid dysfunction remain imperfectly understood. Current evidence suggests that overt and subclinical thyroid dysfunction may cause alterations in lipid levels, in left ventricular size and function, and in endothelial reactivity. These changes may predispose patients to atherosclerosis and to congestive heart failure. The overall hypothesis of this proposal is that abnormal thyroid function is associated with alterations in lipid particle size, in endothelial reactivity, and in cardiac contractility, which result in increased risk for adverse clinical cardiovascular outcomes. In Specific Aim 1, cross-sectional data from the Framingham Heart Study Offspring cohort will be analyzed to determine whether lipid particle size correlates with thyroid function. Additionally, lipid particle subfractions will be measured prospectively in patients who are initially hypothyroid and then become euthyroid after treatment with L-thyroxine to determine whether lipid particle size is altered in overt hypothyroidism. In Specific Aim 2, data from the Framingham original and offspring cohorts will be analyzed longitudinally to determine whether baseline thyroid status predicts cardiovascular disease over follow-up of up to 18 years. In Specific Aim 3, cross-sectional data from the original Framingham cohort will be analyzed to determine whether thyroid function correlates with left ventricular size and function. Data will also be analyzed longitudinally to determine whether baseline thyroid status is an independent predictor of incident congestive heart failure over 16 years of follow-up. Finally, in Specific Aim 4, a clinical study will assess whether L-thyroxine treatment of subclinical hypothyroidism (mild thyroid failure) in patients with congestive heart failure improves echocardiographic markers for left ventricular remodeling and endothelial reactivity. These research projects are designed to provide training in techniques for the cross-sectional and longitudinal analyses of large databases as well as techniques for the design and implementation of clinical studies in an outpatient setting. The pursuit of these projects, in conjunction with formal coursework in biostatistical and epidemiological methods, is intended to foster Dr. Pearce's career as an independent academic clinical investigator with a focus on thyroid disease and epidemiology.